Φλεγμονώδεις Δείκτες στο Σοβαρό Άσθμα Παρόν και Μέλλον Κωνσταντίνος Θ. Κωστίκας, MD, FCCP Πνευμονολογική Κλινική Πανεπιστημίου Θεσσαλίας

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1 . Συνάντηση Ομάδας Άσθματος 2009 Φλεγμονώδεις Δείκτες στο Σοβαρό Άσθμα Παρόν και Μέλλον Κωνσταντίνος Θ. Κωστίκας, MD, FCCP Πνευμονολογική Κλινική Πανεπιστημίου Θεσσαλίας

2 Φλεγμονώδεις Δείκτες στο Σοβαρό Άσθμα Παρόν και Μέλλον In pursuit of biomarkers Bench: the importance of being earnest Bedside: the long and winding road The Future of Biomarkers (?)

3 Φλεγμονώδεις Δείκτες στο Σοβαρό Άσθμα Παρόν και Μέλλον In pursuit of biomarkers Bench: the importance of being earnest Bedside: the long and winding road The Future of Biomarkers (?)

4 Definition of Biomarkers A biomarker has been defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention The term biomarker historically refers to analytes in biological samples Snell E, Curr Opin Pharmacol 2008

5 The ideal biomarker Taylor DR, Pavord ID, Postgrad Med J 2008

6 ΜΗ (ΕΛΑΧΙΣΤΑ) ΕΠΕΜΒΑΤΙΚΕΣ ΜΕΘΟΔΟΙ ΑΞΙΟΛΟΓΗΣΗΣ ΦΛΕΓΜΟΝΗΣ ΑΕΡΑΓΩΓΩΝ Βιοψίες βρογχικού βλεννογόνου Βρογχοκυψελιδικό έκπλυμα (BAL) Έλεγχος βρογχικής υπεραντιδραστικότητας Εκπνεόμενο ΝΟ (FeNO) Προκλητή απόχρεμψη Συμπύκνωμα του εκπνεόμενου αέρα Συστηματικοί δείκτες

7 Pathology of Severe Asthma Phenotypes Early Onset Late Onset Eos (+) Eos ( ) Wenzel SE, AJRCCM 1999; Wenzel SE, AJRCCM 2005

8 Severe Asthma: Evaluation and Steroid Resistance Wenzel SE, AJRCCM 2005 (Perspective)

9 Percent European Network For Understanding Mechanisms Of Severe Asthma (ENFUMOSA) * * Controlled Asthma Severe Asthma Macro Neutro Lymph Eos met br ep sq ep ENFUMOSA, ERJ 2003

10 Biomarkers of Inflammation ENFUMOSA ENFUMOSA, ERJ 2003

11 NHLBI Severe Asthma Research Program (SARP) Plus significant bronchodilator reversibility in severe asthma Moore WC, J All Clin Immunol 2007

12 Serum IL-8 and TNF-α in Severe Asthma Biomarkers of Systemic Inflammation? PLUS increased circulating neutrophils Silvestri M, Clin Exp Allergy 2006

13 hs-crp in EBC and Serum in Severe Asthma PLUS significant correlation between serum and EBC hs-crp Zietkowski Z, Respir Med 2009

14 Φλεγμονώδεις Δείκτες στο Σοβαρό Άσθμα Παρόν και Μέλλον In pursuit of biomarkers Bench: the importance of being earnest Bedside: the long and winding road The Future of Biomarkers (?)

15 Sputum Eosinophilia and Asthma Severity Louis R, AJRCCM 2000

16 Reduced Eosinophil Apoptosis in Severe Asthma Duncan CJA, ERJ 2003

17 Sputum Neutrophilia and Asthma Severity Jatakanon A, AJRCCM 1999

18 Inflammatory Subtypes in Asthma: Sputum Simpson JL, AJRCCM 2005

19 Eosinophils and Neutrophils in Severe Asthma: Associations with Airway Cytokine Profile Severe (n=24) and moderate asthma (n=26) Subjects with severe asthma had more sputum neutrophilia (p=0.007) and eosinophilia (p=0.001) Exhaled nitric oxide was similar between groups IL-8 and IFN-γ expression were increased and IL-4 expression was decreased in severe asthma compared to moderate disease (p<0.001 for each comparison) Eotaxin and IL-5 expression did not differ between groups Excess neutrophilia may be explained by increased expression of IL-8, but differences in eosinophilia do not appear to be associated with IL-5 and eotaxin expression Shannon J, Chest 2008

20 Persistent Airflow Limitation in Severe Asthma Ten Brinke A, AJRCCM 2001

21 Sputum eosinophils and severe asthma Exacerbations and Duration of Asthma Most subjects with high sputum eosinophil counts did not have high mucosal eosinophil counts Exhaled NO was increased in the eosinophilic phenotype as judged from bronchial biopsy findings, but not on the basis of induced sputum No differences in the clinical characteristics between eosinophilic and non-eosinophilic phenotypes Lemière C, JACI 2006

22 Sputum 8-Isoprostane in Severe Asthma Wood LG, AJRCCM 2005

23 Loss of Sputum LXA4 in Severe Asthma Vachier I, J All Clin Immunol 2005

24 GM-CSF in Sputum in Severe Asthma and COPD: Association with Eosinophilic Inflammation Saha SK, Thorax 2009

25 The Origin of Exhaled NO Macrophage IL-8 + TNF-α Exhaled NO NO AIRWAY T-lymphocyte IL-4 + IFN-γ NF-kB NO inos EPITHELIAL CELL Vasodilatation Plasma leakage NO BRONCHIAL MUCOSA Bronchodilation? Eosinophilic inflammation Kharitonov SA, Am J Respir Crit Care Med 2001

26 Severe Asthma in School-Age Children Fitzpatrick AM, JACI 2006 (NHLBI Severe Asthma Research Programme)

27 Alveolar NO in Severe Asthma on CS Brindicci C, Chest 2007

28 Persistent Airflow Obstruction in Severe Asthma Group S: persistent airflow obstruction (FEV1 <50%) Group N: no obstruction (FEV1 >80%) Bumbacea C, ERJ 2004

29 FeNO and Lung Function Decline in Difficult to Treat Asthma Van Veen IH, ERJ 2008

30 NO and ph in Severe Asthma Tseliou E, ERS 2006

31 Nitrotyrosine and Leukotrienes in EBC Hanazawa T, AJRCCM 2000

32 CysLTs and 8-Isoprostane in EBC Samitas K, Respir Med 2009

33 Asthmatic Smokers: Common Mechanisms with COPD? Not all that comes out is hot air Baydur A, Chest 2005 (EDITORIAL) Kostikas K, Chest 2005

34 CysLTs in EBC and RBM thickness 29 children with moderate to severe persistent asthma Lex C, Respir Res 2007

35 Re-Modelling

36 Φλεγμονώδεις Δείκτες στο Σοβαρό Άσθμα Παρόν και Μέλλον In pursuit of biomarkers Bench: the importance of being earnest Bedside: the long and winding road The Future of Biomarkers (?)

37 FeNO to Guide Treatment in Chronic Asthma 45.6% reduction in exacerbation rate (p=0.27) 40% ICS reduction (270 μg/day) (p=0.008) Smith AD, NEJM 2005

38 FeNO for Asthma Management: 46 weeks RCT FeNO Management resulted in higher doses of ICS, without clinically important improvements in symptomatic asthma control BUT included pts. with low FeNO AND Was more efficient in pts with: BMI >30 kg/m 2 high blood eosinophils atopy high total IgE Szefler SJ, Lancet 2008

39 Omalizumab (Xolair ) and FeNO Steroid Stable Phase Steroid Reduction Phase Open-Label Silkoff P, Pediatrics 2004

40 FeNO and persistent eosinophilic phenotype in Severe Refractory Asthma 17 controls 15 pts. mild-moderate asthma 24 pts. severe refractory asthma (SRA) Correlation of FeNO with tissue eosinophils only in pts with SRA r s = 0.54, p = FeNO values >72.9 ppb predict the presence of tissue eosinophilia Sensitivity Specificity 1.0 (AUC=0.83) Silkoff PE, J All Clin Immunol 2005

41 Exhaled breath analysis: current state of standardization, research, and clinical use Kharitonov SA & Barnes PJ, Chest 2006

42 Refractory Eosinophilia in Severe Asthma: Effect of IM Triamcinolone Ten Brinke A, AJRCCM 2004

43 Παροξύνσεις και ηωσινόφιλα πτυέλων 74 ασθενείς από ιατρείο άσθματος (κυρίως ανθιστάμενο στη θεραπεία άσθμα) Randomised, blinded, parallel group, 12 month Σύγκριση "παραδοσιακής" θεραπείας και αντιμετώπισης με επιπρόσθετο στόχο την επαναφορά των ηωσινοφίλων των πτυέλων σε φυσιολογικά επίπεδα Primary outcome: αριθμός σοβαρών παροξύνσεων Green RΗ, Lancet 2002

44 Παροξύνσεις και ηωσινόφιλα πτυέλων SYMPTOMS CONTROLLED anti-inflammatory Rx bronchodilator Rx Sputum guidelines group Sputum eosinophils <1% SYMPTOMS NOT CONTROLLED anti-inflammatory Rx bronchodilator Rx No change in anti-inflammatory Rx bronchodilator Rx Sputum eosinophils 1-3% No change in anti-inflammatory Rx bronchodilator Rx anti-inflammatory Rx bronchodilator Rx Sputum eosinophils >3% anti-inflammatory Rx bronchodilator Rx if on maximum anti-inflammatory Rx Green RΗ, Lancet 2002

45 Σοβαρές παροξύνσεις Παροξύνσεις και ηωσινόφιλα πτυέλων 120 Θεραπεία με βάση συμπτώματα και λειτουργικό έλεγχο Θεραπεία με βάση τα ηωσινόφιλα των πτυέλων % μείωση παροξύνσεων *p = Χωρίς αύξηση κορτικοστεροειδών Μήνες Green RΗ, Lancet 2002

46 Παροξύνσεις και ηωσινόφιλα πτυέλων (2) 49% μείωση παροξύνσεων Ηωσινοφιλικές Μη ηωσινοφιλικές Χωρίς αύξηση κορτικοστεροειδών Jarayam L, Eur Respir J 2006

47 Asthma Management by Monitoring Sputum Neutrophil Counts A Light at the End of the Tunnel of Inflammation in Obstructive Airway Diseases? Gibson PG, Chest 2008 (EDITORIAL) Pallan S, Chest 2008

48 Macrolides in Severe Refractory Asthma Simpson JL, AJRCCM 2007

49 Tiotropium and Non-Eosinophilic Severe Asthma n=17 patients with severe asthma Iwamoto H, ERJ 2008 (Letter to the Editor)

50 Anti-TNF-α (Etanercept) in Severe Asthma Berry M, NEJM 2006

51 Mepolizumab in Refractory Eosinophilic Asthma Haldar P et al. N Engl J Med 2009;360:

52 Φλεγμονώδεις Δείκτες στο Σοβαρό Άσθμα Παρόν και Μέλλον In pursuit of biomarkers Bench: the importance of being earnest Bedside: the long and winding road The Future of Biomarkers (?)

53 Φαινότυποι Άσθματος Πρώιμης Έναρξης Fixed obstruction Severe Exacerbation prone Eosinophilic corticosteroid responsive Exercise-induced Allergic Wenzel SE, Lancet 2006

54 Φαινότυποι Άσθματος Όψιμης Έναρξης PMA Allergic Aspirin-sensitive Severe Eosinophilic corticosteroid-responsive Occupational Non-allergic PMA: perimenstrual asthma Wenzel SE, Lancet 2006

55 . A plea to abandon asthma as a disease concept "So why wait? Rather than confusing scientists, doctors, and patients even further, is it not time to step out of the straightjacket of a seemingly unifying name that has outlived its usefulness? The conclusion should surely be that it is best to abolish the term asthma altogether." The Editor, Lancet 2006; 368: 705 (Editorial)

56 Algorithm for Assessment of Airways Disease Pavord ID, Shaw DE, Gibson PG, Taylor DR; Lancet 2008

59 I don't know what you guys are measuring, but you sure are measuring it McCreanor J, NEJM 2007

60 Breath omics (proteomics, metabolomics et al.) Gray RD, AJRCCM 2008; Carraro S, AJRCCM 2007

61 An Electronic Nose in Severe Asthma Dragonieri S, J All Clin Immunol 2007

62 Early Detection and (perhaps) Prevention (?) Allergic rhinitis and smoking Tanou K, Clin Exp All 2009

64 We have come so far, we have seen so much but there is so much more to do Obama B, Chicago IL, November 5 th 2009

66 Non-Invasive Assessment of Airways Inflammation Edited by S. Loukides, K. Kostikas and P.J. Barnes Book Chapter Exhaled Biomarkers: Where do we stand today? Towards Normal Values Exhaled NO Induced Sputum Exhaled Breath Condensate Technical Considerations Exhaled NO Induced Sputum Exhaled Breath Condensate Application in Clinical Practice: Asthma Exhaled NO in Asthma Induced Sputum in Asthma Exhaled Breath Condensate in Asthma Exhaled Biomarkers in Children Application in Clinical Practice: COPD Exhaled NO in COPD Induced Sputum in COPD Exhaled Breath Condensate in COPD Other Exhaled Biomarkers Perspective: Can Non-Invasive Biomarkers Replace the Invasive Assessment of Airways Inflammation? The Future of Biomarkers Contributor S. Kharitonov A-C Olin, D. Robin Taylor R. Louis S. Loukides, K. Kostikas L. Gustfason A. Spanevello I. Horvath L. Dupont I. Pavord J. Hunt E. Paraskakis, A. Bush M. Corradi N. Rovina, P. Bakakos P. Montuschi P. Paredi, K. Paschalaki Μ Gaga, E. Zervas P.J. Barnes

67 Re-Modelling

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